Antisense inhibition of the PTI-1 oncogene reverses cancer phenotypes.
The genetic alterations and molecular events mediating human prostate cancer development and progression remain to be defined. Rapid expression cloning and differential RNA display detect a putative oncogene, prostate tumor-inducing gene 1 (PTI-1), that is differentially expressed in human prostate (as well as breast, colon, and small cell lung) cancer cell lines, patient-derived prostate carcinomas, and blood from patients with metastatic prostate cancer. PTI-1 consists of a unique 5' untranslated region (5' UTR) with significant sequence homology to Mycoplasma hyopneumoniae 23S ribosomal RNA juxtaposed to a sequence that encodes a truncated and mutated human elongation factor 1alpha (Trun-EF). Stable expression of a nearly full-length 1.9-kb PTI-1 gene, but not the separate PTI-1 5' UTR or Trun-EF region, in normal rat embryo fibroblast cells, CREF-Trans 6, induces an aggressive tumorigenic phenotype in athymic nude mice. Blocking PTI-1 expression with antisense PTI-1 results in reversion of transformed PTI-1-expressing cells to a more normal cellular morphology with suppression in both anchorage-independent growth and tumorigenic potential in athymic nude mice. These findings document that PTI-1 is indeed an oncogene, and directly blocking PTI-1 expression can nullify cancer phenotypes. In these contexts, PTI-1 not only represents a gene with discriminating diagnostic properties but also may serve as a target for the gene-based therapy of human prostate and other cancers.
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Departments of Pathology and Urology, Herbert Irving Comprehensive Cancer Center, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
Goldstein
N I
NI
Fisher
P B
PB
D000818:Animals; D002455:Cell Division; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D005799:Genes, Dominant; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D015513:Oncogene Proteins / Q000235:genetics*; D009857:Oncogenes; D020648:Peptide Elongation Factor 1; D010445:Peptide Elongation Factors / Q000235:genetics; D010641:Phenotype; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology*; D014176:Protein Biosynthesis; D016372:RNA, Antisense; D012334:RNA, Neoplasm / Q000235:genetics; D014162:Transfection
C094814:EEF1A1 protein, human; D015513:Oncogene Proteins; D020648:Peptide Elongation Factor 1; D010445:Peptide Elongation Factors; D016372:RNA, Antisense; D012334:RNA, Neoplasm